Interferon-gamma-mediated inhibition of serum response factor-dependent smooth muscle-specific gene expression.

ABSTRACT: IFN? exerts multiple biological effects on effector cells by regulating many downstream genes, including smooth muscle-specific genes. However, the molecular mechanisms underlying IFN?-induced inhibition of smooth muscle-specific gene expression remain unclear. In this study, we have shown that serum response factor (SRF), a common transcriptional factor important in cell proliferation, migration, and differentiation, is targeted by IFN? in a STAT1-dependent manner. We show that the molecular mechanism by which IFN? regulates SRF is via activation of the 2-5A-RNase L system, which triggers SRF mRNA decay and reduced SRF expression. As a result, decreased SRF expression reduces expression of SRF target genes such as smooth muscle ?-actin and smooth muscle myosin heavy chain. Additionally, IFN? reduced p300 and acetylated histone-3 binding in both smooth muscle ?-actin and SRF promoters, epigenetically decreasing smooth muscle ?-actin and SRF transcriptional activation. Our data reveal that SRF is a novel IFN?-regulated gene and further elucidate the molecular pathway between IFN?, IFN?-regulated genes, and SRF and its target genes.

SUBMITTER: Shi Z 

PROVIDER: S-EPMC2952243 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature